As used herein, "electrotransport" refers generally to the delivery of at least one agent or drug (charged, uncharged, or mixtures thereof) through a membrane (such as skin, mucous membrane, or nails) wherein the delivery is at least partially electrically induced or aided by the application of an electric potential. As used herein, the terms "drug" and "agent" are used interchangeably and are intended to include any therapeutically active substance that when delivered into a living organism produces a desired, usually beneficial, effect. For example, a beneficial therapeutic agent may be introduced into the systemic circulation of a patient by electrotransport delivery through the skin.
Electrotransport processes have been found to be useful in the transdermal administration of drugs including lidocaine, hydrocortisone, fluoride, penicillin, dexamethasone, and many other drugs. A common use of electrotransport is in diagnosing cystic fibrosis by delivering pilocarpine iontophoretically. The pilocarpine stimulates production of sweat. The sweat is then collected and analyzed for its chloride content to detect the presence of the disease. More recently, "reverse" electrotransport methods have been used to transdermally extract body analytes such as glucose in order to measure blood glucose levels. For a description of reverse iontophoresis devices and methods for analyte sampling, see Guy et al. U.S. Pat. No. 5,362,307, the disclosures of which are incorporated herein by reference.
Electrotransport devices generally employ two electrodes, each positioned in intimate contact with some portion of the patient's body (e.g., the skin). For drug delivery, an active or donor electrode delivers the therapeutic agent (e.g., a drug) into the body. The counter, or return, electrode closes an electrical circuit with the donor electrode through the patient's body. A source of electrical energy, such as a battery, supplies electric current to the body through the electrodes. For example, if the therapeutic agent to be delivered into the body is positively charged (i.e., cationic), the anode is the donor electrode and the cathode is the counter electrode completing the circuit. If the therapeutic agent to be delivered is negatively charged (i.e., anionic), the cathode is the donor electrode and the anode is the counter electrode. The rate of drug delivery is generally proportional to the applied electrotransport current. For that reason, commonly used electrotransport systems employ electric circuitry that control the electric current applied by such devices. For body analyte extraction, an active or sampling electrode extracts the body analyte from the body. The counter, or return, electrode closes the electrical circuit with the active electrode through the patient's body. If the body analyte to be extracted from the body is cationic, the cathode is the active electrode and the anode is the counter electrode completing the circuit. If the body analyte to be extracted is anionic, the anode is the active electrode and the cathode is the counter electrode. In the case of glucose extraction, glucose being an uncharged molecule, either or both of the anode and cathode can be the active electrode. Since glucose will be extracted into both electrodes at relatively the same rate by the phenomenon of electroosmosis.
A widely used electrotransport process, iontophoresis (also called electromigration), involves the electrically induced transport of charged ions. Another type of electrotransport, called electroosmosis, involves the transdermal flow of a liquid solvent, containing an (eg, uncharged or non-ionic) agent to be delivered or sampled, under the influence of the applied electric field. Still another type of electrotransport process, called electroporation, involves forming transiently existing pores in a biological membrane (e.g., the skin) by applying high voltage pulses thereto. In any given electrotransport system, more than one of these processes may occur simultaneously to some extent.
Most transdermal electrotransport devices have an anodic and a cathodic electrode assembly, each electrode assembly being comprised of an electrically conductive electrode in ion-transmitting relation with an ionically conductive liquid reservoir which in use is placed in contact with the patient's skin. Gel reservoirs such as those described in Webster U.S. Pat. No. 4,383,529 are the preferred form of reservoir since hydrated gels are easier to handle and manufacture than liquid-filled containers. Water is by far the preferred liquid solvent used in such reservoirs, in part because many drug salts are water soluble and in part because water has excellent biocompatability, making prolonged contact between the hydrogel reservoir and the skin acceptable from an irritation standpoint.
The electrodes used in transdermal electrotransport devices are generally of two types; those that are made from materials that are not electrochemically reactive and those that are made from materials that are electrochemically reactive. Electrochemically non-reactive electrodes, such as stainless steel, platinum, and carbon-based electrodes, tend to promote electrochemical oxidation or reduction of the liquid solvent at the electrode/reservoir interface. When the solvent is water, the oxidation reaction (at the anodic electrode interface) produces hydronium ions, while the reduction reaction (at the cathodic interface) produces hydroxyl ions. Thus, one serious disadvantage with the use of electrochemically non-reactive electrodes is that pH changes occur during device operation due to the water oxidation and reduction reactions which occur at the electrode/reservoir interfaces. Oxidation and reduction of water can largely be avoided by using electrochemically reactive electrodes, as discussed in Phipps et al. U.S. Pat. No. 4,747,819. Preferred electrochemically oxidizable materials for use in the anodic electrode include metals such as silver, copper and zinc. Of these, silver is most preferred, as it has better biocompatability compared to most other metals. Preferred electrochemically reducible materials for use in the cathodic electrode include metal halides. Of these, silver halides such as silver chloride are most preferred. While these electrode materials provide an elegant solution to the problem of pH drift in the electrotransport reservoirs, they have their own set of problems. For example, a silver anode is oxidized to produce silver ions (Ag.fwdarw.Ag.sup.+ +e.sup.-). The silver cations are delivered from the anode via iontophoresis into the patient's skin, where they cause grey or black discoloration as soon as the skin is exposed to sunlight. Attempts have been made to limit the electromigration of electrochemically generated silver ions from the anodic electrode. See for example Phipps et al. U.S. Pat. No. 4,747,819 and Phipps et al. WO 96/39224 which disclose using a halide drug salt in the anodic reservoir to provide halide ions which react with the electrochemically-generated silver ions to produce substantially insoluble silver halides, thereby preventing silver ions from migrating into the skin. See also Phipps et al WO 95/27530 which discloses using a halide resin in the anodic reservoir to provide halide ions which react with the electrochemically-generated silver ions to produce substantially insoluble silver halides, thereby preventing silver ions from migrating into the skin. Unfortunately, both of these approaches to preventing silver ion migration into the skin have their own disadvantages. For the first approach described in Phipps et al. U.S. Pat. No. 4,747,819 and Phipps et al. WO 96/39224, sometimes very large or "excess" amounts of halide drug salt must be loaded into the anodic reservoir in order to provide enough halide ions to prevent silver migration, particularly over longer drug delivery periods. This is disadvantageous because of the high cost of many drugs, thereby making this a costly solution to the silver migration problem. For the second approach described in Phipps et al WO 95/27530, the halide resins have been found to contain many impurities and unreacted monomeric components which cannot effectively be removed from the resins. At least some of these components have been found to cause undesireable skin irritation when the resins are used in electrotransport reservoirs, perhaps because the impurities are being transdermally delivered into the skin by the applied electrotransport current.
One potential solution to the metal ion migration problem encountered with oxidizable metal anodes is the use of intercalation compounds as taught in Phipps, et al, U.S. Pat. Nos. 4,747,819 and 5,573,503. While the use of intercalation compounds does avoid the problem of migration of metal ions into the patient's skin, at least some of these materials (e.g., polyanilines) have not been extensively used, in part because of their very high initial (i.e., at the time the electrotransport device begins applying electrotransport current) electrical resistance. The problem of high electrical resistance is discussed in more detail below in connection with prior art silver halide cathodes.
Hence, there is a need for an improved anodic electrode which does not have the problems of (1) competing metal ion generation as is found in anodes formed of conventional oxidizable metals, and/or (2) high initial electrical resistance.
On the cathode side, the silver halide cathodes produce only halide (eg, chloride) ions when they are electrochemically reduced (AgX.fwdarw.Ag+X.sup.-). Although the electrochemically generated halide (e.g., chloride) ions do tend to be delivered from the cathode into the patient, chloride is naturally present in the body in fairly high amounts so delivery of chloride ions from the cathode has no adverse effects. Thus, while the silver halide cathodes are quite biocompatible, they have one serious disadvantage in that they are substantially non-conductive, at least until enough of the silver halide has been reduced to form metallic silver. This is similar to the problem of high initial electrical resistance found in anodes formed of intercalation compounds such as polyanilines, which anodes don't conduct significant amounts of electric current until enough of the, eg, polyaniline has been oxidized. This may cause a delay in the start of compliant device operation because the silver halide cathode and/or the polyaniline anode has too high an electrical resistance for the relatively small voltages supplied by the small (eg, coin cell) batteries which are used to power small patient-worn electrotransport devices. Of course, electrochemical reduction of the silver halide to form metallic silver, and the electrochemical oxidation of the reduced (i.e., leuco) form of polyaniline to form a more conductive (i.e., an oxidized or emaraldine) form of polyaniline gradually takes place at the interface between the electrode and the liquid electrolyte in accordance with the following reactions:
Anodic polyaniline (PA) oxidation: PA.sub.leuco.fwdarw.PA.sub.emaraldine +2H.sup.+ +2e.sup.- PA1 cathodic silver chloride reduction: AgCl+e.sup.-.fwdarw.Ag+Cl.sup.-.
The reduction of the leuco form of polyaniline is discussed in detail in Cushman et al., "Spectroelectrochemical Study of Polyaniline: the Construction of a pH-potential phase diagram", Journal of Electroanalytical Chemistry, 291 (1986), 335-346. Although the formation of metallic silver at the cathode/liquid electrolyte interface and the formation of oxidized polyaniline at the anode/liquid electrolyte interface gradually improves the electrical conductivity of the electrode, it is a fairly slow process. As a result, traditional electrode configurations like that shown in FIG. 1 are undesirable because of their high electrical resistance at the beginning of electrotransport device operation. The electrode assembly 50 shown in FIG. 1 includes a housing 20 with a depression or well 25 which contains an electrode 52, an electrolyte reservoir 53 and a conductive current collector 51. Current collector 51 comprises a portion of the electrical connection between the electrode 52 and the device power source (not shown in FIG. 1), the other portions of the electrical connection include a metal contact (ie, a tab) 58 and a conductive member 72 which could be a metal wire but more typically is formed by depositing a conductive trace on a non-conductive circuit board 18. Initially, electrode 52 has a high electrical resistance, and therefore acts to insulate the conductive current collector 51 from the electrolyte reservoir 53, which is typically a gel. Due to such insulation, insufficient flow of electrons are available to or from the interface 56 between the electrolyte reservoir 53 and the electrode 52, severely inhibiting the oxidation or reduction of the redox material, thus, causing a higher electrical resistance across the electrode 52. That is, there is a large initial voltage drop across the electrode 52.
The electrical resistance of the electrode 52 is calculated from Ohm's Law: R.sub.electrode =.DELTA.V/i, wherein .DELTA.V is the voltage drop across the electrode and i is the applied current. The electrical resistance at one "side" (ie, either the anodic side or the cathodic side) of an electrotransport device is generally considered to be the sum of the resistances of (1) the electrode assembly, and (2) the patient body surface to which the electrode assembly is applied (e.g., the skin). Although the initial skin resistance is generally quite high (e.g., more than about 50,000 ohm-cm).sup.2 when an electrotransport device is first turned on, the skin resistance drops very quickly during the first 2 to 5 minutes of device operation to a level which is well within the compliant range of electrotransport device power sources, which typically apply voltages in the range of 2 to 10 volts. During this period, because it is important that all available energy is used for overcoming the skin's resistance, any excess voltage drop due to a resistive electrode will diminish the current available for therapy. If the electrode resistance is above a predetermined amount, compliance is lacking, which means that the device is unable to apply the prescribed current because the electrode resistance is too great for the limited voltage of the power source. Unfortunately, the electrical resistance of polyaniline anodes and silver halide cathodes does not drop quickly like human skin. Thus, there can be a long wait (e.g., more than 30 minutes) until the electrode resistance drops to a level at which the electrotransport device becomes compliant and can deliver the prescribed electrical current. This delay in reaching device compliance is also referred to as the start-up lag-time). During this start-up lag-time, the anode resistance drops as the, eg, polyaniline, reacts to form electrically conductive oxidized polyaniline, and the cathode resistance drops as the silver halide reacts to form electrically conductive metallic silver. More importantly, the lag time to compliant drug delivery makes the use of polyaniline anodes and silver halide cathodes in electrotransport drug delivery unacceptable for many applications. For example, many applications for transdermal electrotransport drug delivery require a very short lag time to compliance, such as delivery of an anti-migraine drug to treat migraines or delivery of a narcotic analgesic to treat pain.
Of course, the delay in reaching compliant electrotransport device operation can be reduced by increasing the battery voltage, but this requires more (or more expensive) batteries to power the device which undesirably increases the cost of electrotransport drug delivery. The delay in reaching compliant electrotransport device operation can also be overcome by adding electrically conductive fillers, such as powdered metal or carbon, to the intercalation anode or to the silver halide cathode as taught in Myers et al. U.S. Pat. No. 5,147,297. However, this makes the manufacture of these electrodes more difficult since the conductive fillers must have very good and even distribution throughout the electrode matrix and also makes the electrodes more expensive.
Hence, there is a need for an improved electrode for an electrotransport device that achieves compliant agent delivery quickly, without significant voltage drop due to high initial electrical resistance, and without the need for significant power supply voltages or other expensive conductive fillers to overcome any significant initial electrode resistance.